CART-ddBCMA 治疗复发/难治性多发性骨髓瘤受试者的 1 期研究

Relapsed and refractory multiple myeloma (RRMM) is a plasma cell neoplasm defined by progressively refractory disease necessitating chronic and increasingly intensive therapy. Despite recent advances, limited treatment options exist for RRMM. This single-arm, open label phase 1 study aimed to evaluate the safety of novel B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T construct that leverages a completely synthetic antigen-binding domain (CART-ddBCMA), which was specifically engineered to reduce immunogenicity and improve CAR cell surface stability. Thirteen patients 18 years with RRMM who received at least 3 prior regimens of systemic therapy were enrolled in the study. Patients received a single dose of 100 106 CART-ddBCMA (DL1) or 300 106 CART-ddBCMA (DL2) following standard lymphodepleting chemotherapy.

The primary endpoints of the study were to evaluate the incidence of treatment emergent adverse events, including dose-limiting toxicities, and establish a recommended phase 2 dose. Results showed that CART-ddBCMA was well tolerated and demonstrated a favorable toxicity profile. Only 1 case of grade 3 cytokine release syndrome and 1 case of immune effector cell-associated neurotoxicity were reported; both were at DL2 and were manageable with standard treatment.

No atypical neurological toxicities and Parkinson disease-like movement disorders were observed. The maximum tolerated dose was not reached. All infused patients responded to CART-ddBCMA, and 9/12 (75%) patients achieved complete response/stringent complete response. Responses deepened over time, and at the time of last data-cut (median follow-up 56 weeks), 8/9 (89%) evaluable patients achieved minimal residual disease negativity.

In conclusion, the findings demonstrate the safety of CART-ddBCMA cells and document durable responses to CART-ddBCMA in patients with RRMM. This trial was registered at www. clinicaltrials. gov as #NCT04155749.